Despite the fact that muscular dystrophies are caused by mutations in numerous different genes, they share several common features: loss of muscle mass, inflammation and fibrosis, and progressive failure to regenerate. Ultimately, gene replacement or correction will lead to cures, but routine application of these approaches is likely to be decades away. The development of treatments that slow the progression of muscle degeneration will improve the quality and length of life and permit treatment at more advanced stages of the disease. In this application, we propose to test the efficacy of cyclic nucleotide phosphodiesterase (PDE) inhibitors in slowing the degeneration process in dystrophic muscle. PDE inhibitors are key modulators of cyclic GMP (cGMP) mediated pathways and have proven to be effective drug targets in treating several human diseases, including inflammatory airway diseases, intermittent claudication, recurrent stroke and erectile dysfunction. PDE inhibitors, particularly those targeted at PDE5, reduce cardiac hypertrophy and fibrosis in a pressure induced mouse model. We have new evidence that a nitric oxide-stimulated cGMP pathway on the Golgi complex is disrupted in skeletal muscle of mdx mice. We will test the hypothesis that administration of PDE inhibitors to mdx mice will slow the progression of skeletal muscle degeneration. Preliminary evidence suggests that sildenafil, a PDE5 inhibitor, administered in the drinking water improves the dystrophic phenotype. Ultimately, gene or cell therapy approaches combined with drug treatments that stimulate muscle growth and repair by modulation of cGMP pathways could be an effective treatment for muscular dystrophies of various genetic origins. [unreadable] [unreadable] The research proposed here will test FDA-approved drugs (phosphodiesterase inhibitors) for their ability to slow the progression of muscle degeneration in muscular dystrophy. If efficacious, these drugs could quickly be tested for this use in humans since they have already been approved for treatment of other diseases. They may be useful in many different types of muscular dystrophies by improving muscle health and prolonging survival time. [unreadable] [unreadable] [unreadable]